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This chapter discusses the basic concepts and pathogenesis of cancer chemotherapy, including the mutations and alterations in DNA that lead to uncontrolled cell proliferation. It also explores the characteristics of cancer cells and the different approaches to cancer treatment.
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By:Dr. Abdulaziz Bin SaeedanPh.D.Department of Pharmacology E mail: a.binsaeedan@sau.edu.sa Pharmacology – IVPHL-425 Chapter 2:CANCER CHEMOTHERAPY: The basic Concepts
Pathogenesis of Neoplasia DNA is altered via mutagens including chemical carcinogens, viruses, and radiation. This mutations is inherted by at least one cell division (initiation). This mutation mainly lead to activation of proto-oncogene into oncogenes (leading to uncontrolled cell proliferation) and/or inactivation of tumor suppressor genes (leading to resistance to apoptosis.) Once the cell reproduction process is altered, other factors (epigenetic factors ) indirectly allow and promote these cells to proliferate unchecked (promotion) These promoters can be (hormones, co- carcinogens, immunosuppressant…which themselves are non carcinogenic).
• Initiation - point at which an irreversible alteration, usually genetic, is introduced into a target cell. Initiation: (1) is essentially irreversible (2) caused only by carcinogenic compounds (3) occurs rapidly after carcinogen exposure (4) alone does not result in tumor formation • Promotion is the process whereby an initiated tissue or organ develop focal proliferations and it requires the presence of continuous stimulation. Promotion: (1) reversible (2) acts only after exposure to an initiating agent (3) requires repeated administration of a promoter (4) is not carcinogenic in itself
Etiolopathology 50.2 Rang
Apoptosis Programmed cell death Cascade of proteases initiate process
Characteristics of Cancer Cells • The problem: • Cancer cells divide rapidly (cell cycle is accelerated) • They are “immortal” • Cell-cell communication is altered • uncontrolled proliferation • invasiveness • Ability to metastasise
The Goal of Cancer Treatments • Curative • Total irradication of cancer cells • Curable cancers include testicular tumors • Palliative • Alleviation of symptoms • Avoidance of life-threatening toxicity • Increased survival and improved quality of life • Adjuvant therapy • Attempt to eradicate microscopic cancer after surgery • e.g. breast cancer & colorectal cancer
Rx Modalities (Cancer Treatments) • Surgery • Radiotherapy • Chemotherapy • Endocrine therapy (hormonal therapy) • Immunotherapy • Targeted therapy or molecularly targeted therapy: blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than interfering with all rapidly dividing cells - Small molecule inhibitors: Tyrosine kinase inhibitors (e.gimatinib) - Genetic material (RNA or DNA)
Cancer Chemotherapy After completion of mitosis, the resulting daughter cells have two options: (1) they can either enter G1 & repeat the cycle or (2) they can go into G0 and not participate in the cell cycle. Growth fraction - at any particular time some cells are going through the cell cycle whereas other cells are resting. The ratio of proliferating cells to cells in G0, is called the growth fraction. A tissue with a large percentage of proliferating cells & few cells in G0 has a high growth fraction. Conversely, a tissue composed of mostly of cells in G0 has a low growth fraction.
Cell Cycle Specific (CCS) & Cell Cycle Non-Specific Agents (CCNS)
Log kill hypothesis According to the log-kill hypothesis, chemotherapeutic agents kill a constant fraction of cells (first order kinetics), rather than a specific number of cells, after each dose. In other words, at a given dose, in a given tumor the drug will kill a constant % of cells, regardless the tumor size 1.Solid cancer tumors - generally have a low growth fraction thus respond poorly to chemotherapy & in most cases need to be removed by surgery 2. Disseminated cancers- generally have a high growth fraction & generally respond well to chemotherapy
The example shows the effects of tumor burden, scheduling, initiation/duration of treatment on patient survival. The tumor burden in an untreated patient would progress along the path described by the RED LINE – The tumor is detected (using conventional techniques) when the tumor burden reaches 109 cells The patient is symptomatic at 1010-1011 cells Dies at 1012 cells. LOG kill hypothesis
Cancer Chemotherapy Combinations of agents with differing toxicities & mechanisms of action are often employed to overcome the limited cell kill of individual anti cancer agents. Each drug selected should be effective alone 3 advantages of combination therapy: 1. Suppression of drug resistance - less chance of a cell developing resistance to 2 drugs than to 1 drug. 2. Increased cancer cell kill - administration of drugs with different mechanisms of action. 3. Reduced injury to normal cells - by using a combination of drugs that do not have overlapping toxicities, we can achieve a greater anticancer effect than we could by using any one agent alone.
Resistance to Cytotoxic Drugs • Increased expression of MDR-1 gene for a cell surface P-glycoprotein • MDR-1 gene is involved with drug efflux • Drugs that reverse MDR : verapamil, quinidine, cyclosporine • MDR increases resistance to natural drug products including the anthracyclines, vinca alkaloids, and epipodophyllotoxins
General problems with anticancer drugs • Most of them are antiproliferative, i.e. they damage DNA and so initiate apoptosis. • They also affect rapidly dividing normal cells. • This leads to toxicity which are usually severe. • To greater or lesser extent the following toxicities are exhibits by all anticancer drugs.
Proliferating cells are especially sensitive to chemotherapy because cytotoxic drugs usually act by disrupting DNA synthesis or mitosis, cellular activities that only proliferating cells carry out. Unfortunately, toxicity to the anticancer agents is to any rapidly dividing cells. (e.g. bone marrow, hair follicles, sperm forming cells). Chemotherapeutic agents are much more toxic to tissues that have a high growth fraction than to tissues that have a low growth fraction.
Prevention or Management of Drug Induced toxicities • The toxicities of some anticancer drugs can be well anticipated and hence be prevented by giving proper medications • E.g. mesna is given to prevent hemorrhagic cystitis by cyclophosphamide (How? it reacts with the drug metabolite) • Dexrazoxane, is used to reduce the risk of anthracycline-induced cardiomyopathy
